Metabotropic glutamate receptors (mGluRs) belong to a superfamily of G protein coupled receptors. In the central nervous system (CNS), mGluRs modulate glutamatergic neurotransmission and are considered to affect also on dopaminergic and adrenergic neurotransmission. MGluRs have various physiological functions in CNS and are suggested to be involved in a number of neurological disorders. Receptor ligands binding to mGluRs are also considered as potential therapeutic agents. Classic competitive ligands, which are amino acid derivatives, bind to the orthosteric binding site as endogenous glutamate. It is believed that developing highly selective competitive agonists and antagonists for specific mGluR subtypes has been exceedingly difficult, because of the high conservation of the glutamate binding site across members of this receptor family and the restricted structural requirements for pharmacophores that occupy the binding pocket. Another shortcoming of this kind of ligands is that the carboxyl and amino groups make them too polar to penetrate the blood brain barrier. Although these ligands have had and still have important roles in elucidating physiological and pathophysiological properties of mGluRs, their poor selectivity within group presupposes some knowledge of complexity. In addition, their poor CNS penetration limits their candidacy as promising radiotracers for in vivo imaging of mGluRs. Over the last decade, a number of non-competitive mGluR ligands, which are structurally diverse and bind to mGluRs in the allosteric binding sites located in the seven strand transmembrane domain, have been identified. These include negative, positive and neutral allosteric modulators. Modulating mGlu receptor activity through an allosteric binding site is a relatively new strategy with the first example appeared in 1996. Based on these modulators, a number of radiotracers useful for imaging specific metabotropic glutamate receptors have been developed and their in vivo biological properties have been characterized. We have developed five ligands for PET imaging of metabotropic glutamate subgroup 5 receptors and investigated mGluR functions in animal models of different neurodegenerative disorders. In this review we evaluate our data in comparison to the theoretical and experimental aspects of developing selective and sensitive imaging ligands for in vivo imaging. Emphasis will be given to those highly potent and subtype selective allosteric modulators which are good candidates for radiolabeling with fluorine-18 and carbon-11.
Keywords: Allosteric modulator, glutamate, metabotropic glutamate receptor, mGluR5, positron emission tomography, tracer
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